An efficient and rapid synthetic route to biologically interesting pyranochalcone natural products

Article abstract of DOI:10.3390/12071420

An efficient and concise total synthesis of naturally occurring pyranochalcones was achieved from readily available 2,4-dihydroxyacetophenone and 2,4-dihydroxy-6-methoxyacetophenone. The key steps in the synthetic strategy were ethylenediamine diacetate-c

Full text of DOI:10.3390/12071420

Molecules 2007, 12, 1420-1429
molecules
ISSN 1420-3049
http://www.mdpi.org
Full Paper
An Efficient and Rapid Synthetic Route to Biologically
Interesting Pyranochalcone Natural Products
Yong Rok Lee*, Xue Wang and Likai Xia
School of Chemical Engineering and Technology, Yeungnam University, Gyeongsan 712-749, Korea
* Author to whom correspondence should be addressed; Tel: +82-53-8102529; Fax: +82-53-8104631;
E-mail: yrlee@yu.ac.kr
Received: 29 June 2007; in revised form: 10 July 2007 / Accepted: 10 July 2007 / Published: 12 July
2007
Abstract: An efficient and concise total synthesis of naturally occurring pyranochalcones
was achieved from readily available 2,4-dihydroxyacetophenone and 2,4-dihydroxy-6-
methoxyacetophenone. The key steps in the synthetic strategy were ethylenediamine
diacetate-catalyzed benzopyran formation and aldol reactions.
Keywords: Ethylenediamine diacetate, Pyranyl ring formation, Pyranochalcone natural
products, Aldol reaction
Introduction
Pyranochalcones are an abundant subclass of the flavonoids and are widely distributed in nature
[1]. They were primarily isolated from Lonchocarpus utilus or subglaucescens and Pongamia glabra
[2]. Members of the pyranochalcones have been associated with a wide variety of biological activities
such as antimutagenic, antimicrobial, anti-ulcer and antitumor activities and some plants are used in in
China and Europe as traditional medicines [3]. This wide range of biological properties has stimulated
interest in the synthesis of naturally occurring pyranochalcones (Figure 1). Among these, compound 1
was recently isolated from Artocarpus communis which is known as an edible fruit in the Pacific
islands [4]. Some of the molecules isolated from this plant have shown antinephritus activity [5] and as
5-lipoxygenase inhibitors [6]. Pyranochalcone 1 has also been shown to possess potent inhibitory
activity on nitric oxide production in RAW 264.7 mouse macrophage cells [4]. Glabrachromene II (2)
and glabrachalcone (3) were both isolated from Pongamia glabra [7] and Millettia pachycarpa [8].

Molecules 2007, 12
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Pongachalcone I (4) was isolated from Tephrosia deflexa, and it has been shown to have antibacterial
activity [9]. Interestingly, the structure of obovatachalcone isolated from Tephrosia tunicate was
consistent with that of pongachalcone I [10]. Glaychalcones A (5) and B (6) were isolated from
Glycosmis citrifolia, which is used in folk medicine for the treatment of skin itch, scarbies, and ulcers
[11]. Although several synthetic approaches to pyranochalcones have been developed [12], there are
only a few synthetic routes to grabrachalcone (4), pongachalcone I (5) and glychalcone A (6) [13].
However, these synthetic approaches have been limited due to their many reaction steps, harsh
reaction conditions and low yields due to side reactions [13]. In particular, no synthetic approaches to
natural products 1-2 and 6 have been reported.
Figure 1.
R1
O
OH
R2
R3
R
O
R4
1 R=R2=R4=H, R1=R3=OH
2 R=R1=R4=H, R2=R3=OCH2CH2O Glabrachromene II
3 R=R2=H, R1= R3=R4=OCH3,
4 R=OCH3, R1=R2=R3=R4=H
Glabrachalcone
Pongachalcone I = Obovatachalcone
5 R=OCH3, R1=R2=R4=H, R3=OCH3 Glychalcone A
6 R=OCH3, R1=R4=H, R3=R4=OCH3 Glychalcone B
We have reported convergent synthetic routes to naturally occurring pyranochalcones, lonchocarpin
(11) and 4-hydroxylonchocarpin (12) via a key intermediate 10, as shown in Scheme 1 [14]. Although
the overall yield from 7 to benzopyran 10 is satisfactory (5-steps, 45%), more simple and more concise
synthetic routes are still needed. Accordingly, there has been considerable research on improved
synthetic approaches of pyranochalcone derivatives.
Scheme 1.
O
O
O
OH
O
7
O
O
OH
i)
i) NaOH
ii) MeLi
NC
LDA
ii) DDQ
OEt
H
EtO
EDDA
O
O
O
O
O
8
10
9
O
OH
H
11 R=H lonchocarpin
12 R=OH 4-hydroxylonchocarpin
RO
RO
O
LDA
Recently, we developed an efficient and simple methodology for preparing benzopyrans by
ethylenediamine diacetate-catalyzed reactions of resorcinols to α,β-unsaturated aldehydes [15]. These
reactions involve a formal [3+3]-cycloaddition via a 6π-electrocyclization (Scheme 2). To develop an
efficient and rapid synthetic routes to biologically interesting pyranochalcone natural products as

Molecules 2007, 12
1422
shown in Figure 1, we investigated the ethylenediamine diacetate-catalyzed reactions of 2,4-
dihydroxy-acetophenone and 2,4-dihydroxy-6-methoxyacetopheneone with 3-methyl-2-butenal to give
benzo-pyrans as a one-pot procedure. By using synthesized bezopyrans as a key intermediate, we
report herein total synthesis of pyranochalcone natural products 1-6.
Scheme 2.
O
R2
H
OH
OH
OH
R2
R3
R2
R3
R4
R3
R4
EDDA
(10 mol%)
R1
OH
R1
O
R1
O
R4
Results and Discussion
The retrosynthetic strategy for the synthesis of pyranochalcone natural products 1-6 is shown in
Scheme 3. Natural products 1-6 could be prepared from base-catalyzed aldol reactions of benzopyrans
15 and 16 with the corresponding benzaldehydes 17-22. The crucial intermediates 15 and 16 could be
generated from the readily available materials 13 and 14 using ethylenediamine diacetate-catalyzed
benzopyran formation reactions.
Scheme 3. Retrosynthetic analysis of pyranochalcone natural products 1-6.
O
OH
R1
O
R1
O
OH
R2
R2
R3
H
+
R
O
R3
R
O
17-22
15 R=H
R4
R4
16 R=OCH3
1 R=R2=R4=H, R1=R3=OH
2 R=R1=R4=H, R2=R3=OCH2O
3 R=R1=H, R1=R3=R4=OCH3
4 R=OCH3, R1=R2, R3,=R4=H
5 R=R3=OCH3, R1=R2=R4=H
6 R=R2=R3=OCH3, R1=R4=H
O
R
OH
OH
13 R=H
14 R=OCH3
The benzopyran 15 was first prepared starting from 2,4-dihydroxyacetophenone (13) as shown in
Scheme 4. A reaction of 13 with 3-methyl-2-butenal in the presence of 10 mol % of ethylenediamine
diacetate in refluxing toluene for 12 h gave desmethyl isoencecalin (15) in 52% yield, which was
isolated from Blepharispermum subseeile [16]. It has also shown to have strong antifungal,
antibacterial, and anti-implantation activities [17]. To complete the synthesis of natural products, aldol
reactions were next tried. Attempts to condense compound 15 to 2,4-dihydroxybezaldehyde using
KOH in ethanol were unsuccessful. After examining many procedures, a reaction of compound 15
with protected benzopyran 17 using KOH in ethanol at room temperature for 48 h provided compound
23 in 71% yield, which was deprotected with TBAF/HMPA in refluxing THF for 5 h to give

Molecules 2007, 12
1423
compound 1 (89%). The spectral data of compound 1 was in good agreement with that of the natural
product reported in the literature [4]. Reaction of 15 with piperonal 18 using KOH in ethanol at room
temperature for 48 h gave glabrachromene II (2) in 60% yield, whereas treatment with 2,4,5-
trimethoxybenzaldehyde 19 gave glabrachalcone (3) in 73% yield. The spectral data of compounds 2
and 3 was in agreement with that of the natural products reported in the literature [7, 8a].
Scheme 4.
OH
O
OH
OSEM
O
OH
TBAF/THF
HMPA
HO
O
89%
SEMO
O
O
1
23
KOH
EtOH
71%
H
O
SEMO
OSEM
17
O
O
O
OH
O
OH
H
O
O
OH
O
18
H
KOH
EtOH
60%
EDDA
O
O
OH
toluene
52%
2
O
13
15
OMe O
KOH
EtOH
73%
H
19
MeO
OMe
OMe
O
OH
MeO
O
3
OMe
The total synthesis of pongachalcone I (4), and glychalcones A (5) and B (6) was investigated
starting from 2,4-dihydroxy-6-methoxyacetopheneone (14) as shown in Scheme 5. Treatment of 14
with 3-methyl-2-butenal in the presence of 10 mol % of ethylenediamine diacetate in refluxing toluene
for 12 h gave isoevodionol 16 in a yield of 95%, which was isolated from Mariscus pedunculatus and
Evodia lepta [18]. Reaction of compound 16 with benzaldehyde 20 using KOH in ethanol at room
temperature for 48 h afforded pongachalcone I (4) in yield of 87%. The spectral data of our synthetic
material 4 is the same as values reported in the literature [12a]. Treatment of 16 with 4-methoxy-
benzaldehyde 21 using KOH in ethanol gave glychalcone A (5) in 85% yield, whereas reaction with
3,4-dimethoxybenzaldehyde 22 afforded glychalcone B (6) in 82% yield. The spectral data of
compounds 5 and 6 was in good agreement with that of the natural products reported in the literature
1
[11]. Interestingly, in the H-NMR spectrum of compound 5, no doublets were observed for the H-α
and H-β protons of chalcone moiety. These protons gave rise to a singlet at δ 7.76, integrating for 2
protons due to the same chemical shifts of H-α and H-β [19].

Molecules 2007, 12
1424
Scheme 5.
O
OH
H3CO
O
4
O
KOH
EtOH
O
H
H
20
87%
O
OH
O
OH
O
OH
O
MeO
21
H
KOH
EtOH
85%
EDDA
MeO
H3CO
O
H3CO
O
H3CO
OH
toluene
5
14
16
O
95%
H3CO
KOH
EtOH
82%
H
22
H3CO
O
OH
H3CO
H3CO
H3CO
O
6
Conclusions
An efficient and concise total synthesis of biologically interesting pyranochalcone natural products
1-6 was accomplished from readily available 2,4-dihydroxyacetophenone and 2,4-dihydroxy-6-
methoxyacetophenone. The key strategy in the synthetic procedures involves the ethylenediamine
diacetate-catalyzed benzopyran formation and the aldol reactions.
Experimental
General
All the experiments were carried out under a nitrogen atmosphere. Merck precoated silica gel
plates (Art. 5554) with a fluorescent indicator were used for analytical TLC. Flash column
1
13
chromatography was performed using silica gel 9385 (Merck). The H-NMR and C-NMR spectra
were recorded in CDCl3 on a Bruker Model ARX spectrometer (operating at 300 and 75 MHz,
respectively) using δ = 77.0 ppm as the solvent chemical shift. The IR spectra were recorded on a
Jasco FTIR 5300 spectrophotometer. The HRMS and MS spectra were carried out at the Korea Basic
Science Institute.
Desmethylisoencecalin (15) [16]
To a solution of 2,4-dihydroxyacetophenone (13) (456 mg, 3.0 mmol) and 3-methyl-2-butenal (378
mg g, 4.5 mmol) in toluene (20 mL) was added ethylenediamine diacetate (54 mg, 0.3 mmol) at room

Molecules 2007, 12
1425
temperature. The reaction mixture was refluxed for 12 h and then cooled to room temperature. Water
was added and the solution was extracted with ethyl acetate. Evaporation of solvent and purification
by column chromatography on silica gel gave 15 (340 mg, 52%) as a solid: mp 101-103 oC; 1H-NMR δ
12.95 (1H. s), 7.49 (1H, d, J= 8.8 Hz), 6.69 (1H, d, J= 10.0 Hz), 6.31 (1H, d, J= 8.8 Hz), 5.56 (1H, d,
13
J= 10.0 Hz), 2.51 (3H, S), 1.43 (6H, s); C-NMR δ 203.1, 160.1, 160.0, 132.0, 128.6, 116.2, 114.2,
109.6, 108.7, 78.1, 28.7, 26.6; IR (neat) 2976, 2930, 1630, 1618, 1487, 1426, 1366, 1329, 1273, 1211,
1165, 1125, 1071, 896 cm-1.
3-[2,4-Bis-(2-trimethylsilanylethoxy)phenyl]-1-(5-hydroxy-2,2,dimethyl-2H-chromen-6-yl)propenone
(23)
To a solution of 15 (109 mg, 0.5 mmol) in ethanol (10 mL) was added potassim hydroxide (140
mg, 2.5 mmol) and aldehyde 17 (299 mg, 0.75 mmol) at room temperature. The reaction mixture was
stirred for 48 h at room temperature. Evaporation of ethanol and extraction with ethyl acetate (3 x 50
mL), washing with 2N-HCl solution and brine, drying over MgSO4 and removal of the solvent
1
followed by flash column chromatography on silica gel gave 23 (213 mg, 71%) as an oil: H-NMR δ
13.8 (1H, s), 8.15 (1H, d, J= 15.5 Hz), 7.69 (1H, d, J= 8.9 Hz), 7.57 (1H, d, J= 8.7 Hz), 7.77 (1H, d, J=
15.5 Hz), 6.87 (1H, d, J= 2.3 Hz), 6.74 (1H, d, J= 10.0 Hz), 6.71 (1H, dd, J= 8.7, 2.2 Hz), 6.34 (1H, d,
J= 8.9 Hz), 5.57 (1H, d, J= 10.0 Hz), 5.30 (2H, s), 5.24 (2H, s), 3.80-3.69 (4H, m), 1.44 (6H, s), 0.98-
0.90 (4H, m), -0.02 (18H, s); 13C-NMR δ 192.9, 161.3, 161.2, 158.6, 140.1, 131.0, 130.3, 128.5, 118.9,
118.7, 116.4, 114.6, 109.7, 108.5, 103.8, 93.6, 93.1, 78.1, 77.9, 77.8, 77.6, 67.0, 28.7, 18.5, -0.9; IR
(neat) 2955, 1634, 1605, 1485, 1294, 1252, 1117, 1005, 937, 837 cm-1; HRMS m/z (M+) calcd for
C32H46O7Si2: 598.2782. Found: 598.2784.
3”,3”-Dimethylpyrano[3’,4’]-2,4,2’-trihydroxychalcone (1) [4]
To a solution of 23 (120 mg, 0.2 mmol) in THF (10 mL) and HMPA (1 mL) was added TBAF (0.3
mL of 1.0 M in THF, 0.3 mmol) and the mixture was refluxed for 5 h. Water was added and the
solution was extracted with ethyl acetate. Evaporation of solvent and purification by column
1
chromatography on silica gel gave 1 (68 mg, 89%) as a solid: : mp 145-146 oC; H-NMR δ 8.05 (1H,
d, J= 15.5 Hz), 7.69 (1H, d, J= 8.9 Hz), 7.60 (1H, d, J= 15.5 Hz), 7.45 (1H, d, J= 8.5 Hz), 6.73 (1H, d,
J= 10.0 Hz), 6.44 (1H, dd, J= 8.5, 2.2 Hz), 6.36 (1H, d, J= 2.2 Hz), 6.33 (1H, d, J= 8.9 Hz), 5.57 (1H,
d, J= 10.0 Hz), 1.44 (6H, s); IR (KBr) 3441, 2965, 1632, 1614, 1571, 1454, 1376, 1261, 1116, 803,
763 cm-1; HRMS m/z (M+) calcd for C20H18O5: 338.1154. Found: 338.1153.
Glabrachromene II (2) [7]
To a solution of 15 (109 mg, 0.5 mmol) in ethanol (10 mL) was added potassim hydroxide (140
mg, 2.5 mmol) and aldehyde 18 (113 mg, 0.75 mmol) at room temperature. The reaction mixture was
stirred for 48 h at room temperature. Evaporation of ethanol and extraction with ethyl acetate
(3 x 50 mL), washing with 2N-HCl solution and brine, drying over MgSO4 and removal of the solvent
followed by flash column chromatography on silica gel gave 2 (105 mg, 60%) as a solid:

Molecules 2007, 12
1426
mp 119-120 oC;1H-NMR δ 7.72 (1H, d, J= 15.6 Hz), 7.68 (1H, d, J= 9.0 Hz), 7.37 (1H, d, J= 15.6 Hz),
7.14 (1H, s), 7.11 (1H, d, J= 7.9 Hz), 6.82 (1H, d, J= 7.8 Hz), 6.74 (1H, d, J= 10.0 Hz), 6.35 (1H, d, J=
13
9.0 Hz), 6.01 (2H, s), 5.57 (1H, d, J= 10.0 Hz), 1.45 (6H, s); C-NMR δ 191.8, 160.9, 159.7, 150.0,
148.4, 144.1, 130.5, 129.2, 128.1, 125.4, 118.2, 115.9, 114.0, 109.4, 108.7, 108.2, 106.6, 101.7, 77.8,
28.3; IR (KBr)2978, 1634, 1582, 1487, 1449, 1379, 1211, 1113, 1042, 976, 930, 843, 789, 735, 720
cm-1.
Glabrachalcone (3) [8]
To a solution of 15 (109 mg, 0.5 mmol) in ethanol (10 mL) was added potassim hydroxide (140
mg, 2.5 mmol) and aldehyde 19 (147 mg, 0.75 mmol) at room temperature. The reaction mixture was
stirred for 48 h at room temperature. Evaporation of ethanol and extraction with ethyl acetate (3 x 50
mL), washing with 2N-HCl solution and brine, drying over MgSO4 and removal of the solvent
followed by flash column chromatography on silica gel gave 3 (145 mg, 73%) as a solid: mp 130-131
1
oC; H-NMR δ 8.14 (1H, d, J= 15.5 Hz), 7.70 (1H, d, J= 8.9 Hz), 7.49 (1H, d, J= 15.5 Hz), 7.08 (1H,
s), 6.73 (1H, d, J= 10.0 Hz), 6.49 (1H, s), 6.34 (1H, d, J= 8.9 Hz), 5.56 (1H, d, J= 10.0 Hz), 3.92 (3H,
s), 3.89 (6H, s), 1.43 (6H, s); 13C-NMR δ 192.4, 160.9, 159.4, 154.8, 152.6, 143.2, 139.7, 130.5, 128.0,
118.0, 116.0, 115.3, 114.2, 111.5, 109.4, 108.0, 96.6, 77.7, 56.5, 56.3, 56.1, 28.3; IR (KBr) 2977,
1611, 1505, 1468, 1433, 1339, 1279, 1206, 1107, 1026, 923, 847, 805, 728 cm-1.
Isoevodionol (16) [18]
To a solution of 2,4-dihydroxy-6-methoxyacetophenone (14) (364 mg, 2.0 mmol) and 3-methyl-2-
butenal (252 mg g, 3.0 mmol) in toluene (20 mL) was added ethylenediamine diacetate (36 mg, 0.2
mmol) at room temperature. The reaction mixture was refluxed for 12 h and then cooled to room
temperature. Water was added and the solution was extracted with ethyl acetate. Evaporation of
solvent and purification by column chromatography on silica gel gave 16 (472 mg, 95%) as a solid: mp
128-129 oC; 1H-NMR δ 14.01 (1H, s), 6.62 (1H, d, J= 10.0 Hz), 5.85 (1H, s), 5.38 (1H, d, J= 10.0 Hz),
13
3.81 (3H, s), 2.56 (3H, s),1.46 (6H, s); C-NMR δ 203.0, 162.8, 161.7, 160.0, 125.2, 115.9, 105.5,
102.5, 90.5, 78.0, 55.4, 32.9, 28.2; IR (KBr) 2924, 2855, 1620, 1464, 1362, 1269, 1206, 1159, 1125,
891, 831, 731cm-1.
Pongachalcone I (4) [9]
To a solution of 16 (124 mg, 0.5 mmol) in ethanol (10 mL) was added potassim hydroxide (140
mg, 2.5 mmol) and benzaldehyde 20 (80 mg, 0.75 mmol) at room temperature. The reaction mixture
was stirred for 48 h at room temperature. Evaporation of ethanol and extraction with ethyl acetate (3 x
50 mL), washing with 2N-HCl solution and brine, drying over MgSO4 and removal of the solvent
followed by flash column chromatography on silica gel gave 4 (146 mg, 87%) as a solid: mp 105-106
oC;1H-NMR δ 14.70 (1H, s), 7.87 (1H, d, J= 15.6 Hz), 7.76 (1H, d, J= 15.6 Hz), 7.60-7.57 (2H, m),
7.42-7.34 (4H, m), 6.68 (1H, d, J= 10.0 Hz), 5.91 (1H, s), 5.45 (1H, d, J= 10.0 Hz), 3.89 (3H, s), 1.45
(6H, s); 13C-NMR δ 192.5, 162.5, 162.4, 160.3, 142.0, 135.5, 129.9, 128.8, 127.5, 125.2, 122.2, 115.9,

Molecules 2007, 12
1427
105.9, 102.8, 91.4, 78.2, 55.7, 28.3; IR (KBr) 2926, 2855, 1618, 1580, 1451, 1424, 1339, 1287, 1235,
1200, 1148, 1125, 978, 872, 810, 766, 727, 700 cm-1.
Glychalcone A (5) [11]
To a solution of 16 (124 mg, 0.5 mmol) in ethanol (10 mL) was added potassim hydroxide (140
mg, 2.5 mmol) and benzaldehyde 21 (102 mg, 0.75 mmol) at room temperature. The reaction mixture
was stirred for 48 h at room temperature. Evaporation of ethanol and extraction with ethyl acetate (3 x
50 mL), washing with 2N-HCl solution and brine, drying over MgSO4 and removal of the solvent
followed by flash column chromatography on silica gel gave 5 (156 mg, 85%) as a solid: mp 90-91 oC;
1H-NMR δ 14.71 (1H, s), 7.76 (2H, s), 7.55 (2H, d, J= 8.9 Hz), 6.91 (2H, d, J= 8.9 Hz), 6.67 (1H, d, J=
13
10.0 Hz), 5.91 (1H, s), 5.44 (1H, d, J= 10.0 Hz), 3.89 (3H, s), 3.83 (3H, s), 1.43 (6H, s); C-NMR δ
193.0, 167.7, 161.6, 161.3, 155.9, 142.6, 130.2, 128.7, 125.4, 124.8, 117.0, 114.7, 106.6, 103.3, 92.9,
78.0, 55.9, 28.2; IR (KBr) 2975, 1621, 1576, 1512, 1451, 1424, 1260, 1235, 1198, 1173, 1148, 1123,
1063, 1026, 829, 710 cm-1; EIMS m/z 366 (M+, 45), 351 (33), 232 (10), 218 (12), 217 (100).
Glychalcone B (6) [11]
To a solution of 16 (124 mg, 0.5 mmol) in ethanol (10 mL) and water (2 mL) was added potassim
hydroxide (140 mg, 2.5 mmol) and benzaldehyde 22 (125 mg, 0.75 mmol) at room temperature. The
reaction mixture was stirred for 48 h at room temperature. Evaporation of ethanol and extraction with
ethyl acetate (3 x 50 mL), washing with 2N-HCl solution and brine, drying over MgSO4 and removal
of the solvent followed by flash column chromatography on silica gel gave 5 (163 mg, 82%) as a solid:
mp 126-127 oC;1H-NMR δ 14.78 (1H, s), 7.72 (1H, d, J= 15.6 Hz), 7.66 (1H, d, J= 15.6 Hz), 7.14 (1H,
dd, J= 8.4, 2.2 Hz), 7.05 (1H, d, J= 2.2 Hz), 6.82 (1H, d, J= 8.4 Hz), 6.61 (1H, d, J= 10.0 Hz), 5.85
13
(1H, s), 5.40 (1H, d, J= 10.0 Hz), 3.89 (3H, s), 3.86 (3H, s), 3.84 (3H, s), 1.39 (6H, s); C-NMR δ
192.5, 162.5, 160.2, 148.3, 142.3, 130.0, 125.6, 125.3, 125.0, 121.0, 116.1, 109.1, 108.6, 106.7, 101.5,
100.7, 91.5, 79.2, 64.3, 55.9, 28.3; IR (KBr) 2975, 1621, 1576, 1512, 1451, 1424, 1260, 1235, 1198,
1173, 1148, 1123, 1063, 1026, 829, 710 cm-1.
Acknowledgements
This work was supported by grant No. RTI04-01-04 from the Regional Technology Innovation
Program of the Ministry of Commerce, Industry, and Energy (MOCIE).
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Molecules 2007, 12
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